Use of intravenous polyclonal immunoglobulins in autoimmune and inflammatory disorders]

Initially used for the treatment of immunodeficiencies, intravenous immunoglobulins (IVIg) have increasingly been used as immunomodulatory agent in autoimmune and inflammatory disorders. The mode of action of IVIg is enigmatic, probably involving Fc-dependent and/or F(ab')2-dependent non-exclusive mechanisms of action. IVIg broadly interacts with the different components of the immune system: cytokines, complement, Fc receptors and several cell surface immunocompetent molecules. IVIg also has an impact on effector functions of immune cells. These mechanisms of action of IVIg reflect the importance of natural antibodies in the maintenance of immune homeostasis. We discuss here the recent advances in the understanding of immunoregulatory effects of IVIg, and we pointed out the need of new strategies to overcome the predicted increasing worldwide shortage of IVIg.     

Modulatory effect of intravenous immunoglobulin on Th17/Treg cell balance in women with unexplained recurrent spontaneous abortion

Recurrent spontaneous abortion (RSA) is a growing problem worldwide. In a majority of cases, the cause remains unknown but there is increasing evidence that immunologic factors play an important role. Intravenous immunoglobulin (IVIg) therapy has been proposed to have immune modulatory effects and therefore been applicable for the treatment of patients with RSA. Although its efficacy is still controversial, several recent studies suggest that IVIg treatment may improve pregnancy outcomes. CD4⁺ T cells and their related cytokines play an important role in maternal‐fetal immune regulation, and an imbalance of Th17/Treg cell ratio has been proposed as a cause for RSA. We review the scientific evidence supporting a modulatory effect of IVIg on Th17/Treg cell balance and discuss the potential mechanisms how IVIg might enhance Treg cells function. We propose that correction of Th17/Treg cell dysregulation could be one of the mechanisms that can explain the positive therapeutic effects of IVIg therapy. Consequently, selecting patients with abnormal Th17/Treg cell ratios could increase the success of IVIg therapy.     

Modulation of the cellular immune system by intravenous immunoglobulin

Intravenous immunoglobulin (IVIg) is therapeutically used in a variety of immune-mediated diseases. The beneficial effects of IVIg in auto-antibody-mediated diseases can be explained by neutralization, accelerated clearance and prevention of Fcgamma-receptor binding of auto-antibodies. However, the means by which IVIg exerts therapeutic effects in disorders mediated by cellular immunity have remained enigmatic. Clinical improvements, followed by IVIg treatment, often extend beyond the half-life of infused IgG, thereby indicating that IVIg modifies the cellular immune compartment for a prolonged period. Here, we discuss recent advances in the understanding of different, mutually non-exclusive mechanisms of action of IVIg on cells of the innate and adaptive immune system. These mechanisms might explain the beneficial effects of IVIg in certain autoimmune and inflammatory diseases.     

B cells are resistant to immunomodulation by 'IVIg-educated' dendritic cells

Intravenous immunoglobulin (IVIg) can exert beneficial effects in autoimmune and inflammatory diseases via several mutually non-exclusive mechanisms. While, IVIg can directly modulate the functions of both innate and adaptive immune cells such as dendritic cells (DC), macrophages, B and T cells, several reports have also highlighted that the regulation of immune responses by IVIg can be indirect. In view of these results, we aimed at exploring whether indirect regulation of immune cells by 'IVIg-educated' innate cells is a universal phenomenon. We addressed this question by deciphering the modulation of B cell functions by 'IVIg-educated' DC. Our results indicate that human B cells are resistant to immunomodulation by 'IVIg-educated' DC. However, IVIg at therapeutic concentrations can directly inhibit B cell activation and proliferation. These results thus suggest that, indirect modulation of immune cells by IVIg is not a universal phenomenon.     

The mechanisms of action of IVIG in autoimmune and inflammatory diseases

Human intravenous immunoglobulin (IVIg) is constituted by pooled immunoglobulin (IgG) from several thousand healthy donors. IVIg consists of antibodies to external antigens and naturally occurring autoantibodies (NAbs) with germline or close to germline configurations. The NAbs are independent of deliberate immunization with cognate antigens. It is well established that NAbs play an important role in maintaining tissue and immune homeostasis. It is therefore logical to attribute the therapeutic beneficial effects of IVIg to NAbs. Apart from immunodeficiency conditions, IVIg is indicated for the treatment of a variety of autoimmune and inflammatory conditions. Despite its use in a wide range of autoimmune and inflammatory conditions, the mechanisms underlying the beneficial effects have not been fully elucidated. Understanding the mechanisms by which IVIg operates under different clinical settings is of critical significance. In this review, we summarize the current status of the mechanisms of action of IVIg in autoimmunity and the recent advances in IVIg therapy.     

Facing the enigma of immunomodulatory effects of intravenous immunoglobulin

Intravenous immunoglobulin (IVIg) is a safe remedy for a number of conditions; it is produced from human plasma of thousands of healthy donors. The therapeutic effect of IVIg lies within its content. IVIg contains natural antibodies, which are more polyreactive than immune antibodies, including immunoglobulin G antibodies against endogenous and exogenous antibodies, immunomodulating peptides, and varies cytokines. Beneficial effects of IVIg have been established in immunodeficiencies, as well as in some autoimmune diseases. Also, numerous therapeutic effects of IVIg have been reported over the years in varies autoimmune diseases, recurrent pregnancy loss, and cancer. Many proposed immunoregulatory mechanisms of action of IVIg have been suggested. Some of them have been proven, others are still an enigma, at least in part. Some of these mechanisms entail (a) Fc-receptor blockade; (b) neutralization of pathogenic autoantibodies via idiotypic and anti-idiotypic antibodies; (c) effects on the Fas apoptotic pathway via agonistic and antagonistic anti-Fas autoantibodies; (d) regulation of complement components; (e) modulation of cytokine secretion; (f) hindrance of natural-killer cell activity; (g) inhibition of matrix metalloproteinase-9; (h) suppression of NFkB activation and IkB degradation; (i) G1 cell cycle arrest; (j) prevention of tumor growth; (k) decrease in leukocyte recruitment; (l) attenuation of T-cell stimulation; (m) effects on antibody kinetics; and (n) effects on dendritic cells. The variant mechanisms of IVIg are believed to cooperate in a synergistic way, which all together point to IVIg as a therapeutic preparation with anti-inflammatory, antiself-reactivity, antimetastatic, and embryo-protective effects. This article reviews several main mechanisms of IVIg in order to shed some light on the set of therapeutic effects of IVIg, which are not yet fully understood.     

Therapeutic intravenous immunoglobulins

Intravenous immunoglobulins (IVIg) are concentrated formulations of human IgG prepared by industrial fractionation of large pools of individual plasma donations. IVIg were developed 20 years ago for the prophylaxis support of immunodeficient patients. However, IVIg have been increasingly used since 10 years, in the treatment of many autoimmune and inflammatory diseases raising the possibility of product shortages and ever increasing costs in the near future. Surprisingly, the immunomodulatory mechanisms of action of IVIg are unclear because of the diversity and often contradictory Fc, F(ab')(2), and non-IgG-related mechanisms that have been proposed from clinical observations and from results obtained in various in vitro and in vivo experimental models. These concepts are reviewed here and we discuss in more details three areas of active research, namely the mechanisms of IVIg action in Idiopathic Thrombocytopenic Purpura (ITP), the effects of IVIg on activated B lymphocytes and the possible involvement of autoantibodies of IgG isotype (auto-IgG) in the immunomodulatory effects of IVIg. The elucidation of the mechanisms of action of IVIg is crucial for a more rationalized clinical use of IVIg and for developing substitutes for some of the immunomodulatory indications in order to ensure long-term availability of plasma-derived IVIg for immunodeficient patients.     

Human polyspecific immunoglobulin for therapeutic use induces p21/WAF-1 and Bcl-2, which may be responsible for G1 arrest and long-term survival

High-dose intravenous immunoglobulin (IVIg) is used as therapy in an increasing number of immune mediated disorders including infections and autoimmune conditions. IVIg exerts profound effects both in vivo as well as in vitro on humoral and cell-mediated immunity. In this study we investigated whether IVIg could alter the pattern of apoptosis and apoptosis related proteins including Bcl-2, Bax, p53, CD95, and p21/WAF-1, a protein well known to arrest cells in G1 phase of the cell cycle and finally proliferation marker Ki-67 on peripheral blood mononuclear cells (PBMC). The cells were cultured either unstimulated or with mitogen in the presence or absence of different IVIg preparations. A dual effect by IVIg was found. The incidence of apoptosis was elevated in activated Ki-67 and CD95 positive PBMC, whereas it was lower in small, nonactivated cells. The cells that survived were associated with a striking increase in the expression of p21/WAF-1 suggesting G1 arrest. A concomitant upregulation of Bcl-2 was also obtained by IVIg exposition resulting in long-term survival. We suggest that these abilities of IVIg to alter cell cycle progression and apoptosis could explain some of the beneficial effects obtained in vivo with IVIg therapy.     

Sialylation may be dispensable for reciprocal modulation of helper T cells by intravenous immunoglobulin

Several mechanisms account for the beneficial effect of intravenous immunoglobulin (IVIg) in autoimmune and inflammatory diseases. These mechanisms include effects on the cellular compartment and on the humoral compartment. Thus, IVIg impacts on dendritic cells, macrophages, neutrophils, basophils, NK cells, and B and T lymphocytes. Several studies have emphasized that the antiinflammatory effect of IVIg is dependent on α2,6‐sialylation of the N‐linked glycan on asparagine‐297 of the Fc portion of IgG. However, recent reports have questioned the necessity of sialylated Fc and the role of FcγRIIB in IVIg‐mediated antiinflammatory effects. In view of the critical role played by Th17 cells in several autoimmune pathologies and the increasing use of IVIg in several of these conditions, by using neuraminidase‐treated, desialylated IVIg, we addressed whether the α2,6‐sialylation of IgG is essential for the beneficial effect of IVIg in experimental autoimmune encephalomyelitis (EAE), a Th17‐driven condition, and for the reciprocal modulation of helper T‐cell subsets. We observed no difference in the ability of IVIg to ameliorate EAE irrespective of its sialylation. Our findings thus show that sialylation of IVIg is not necessary for IVIg‐mediated amelioration of EAE or for downregulation of Th17 cells and upregulation of regulatory T cells.     

Neutralization of mitogenic lectins by intravenous immunoglobulin (IVIg) prevents T cell activation: does IVIg really have a direct effect on T cells?

Intravenous immunoglobulin (IVIg) is used for the treatment of an increasing number of autoimmune diseases. Clinical observations on IVIg-treated patients have revealed a modulation of T cell populations and functions in these patients. In vitro studies aimed at understanding the mechanisms underlying the effects of IVIg on T cells led to the conclusion that IVIg directly affected lectin-activated T cell functions. However, more recent studies have suggested the absence of a direct effect of IVIg on T cells. In the present work, we revisited the effect of IVIg on T cells using lectin-stimulated human T cells and showed that IVIg inhibited T cell functions only when added simultaneously with the activating lectin. Further, we showed that IVIg depleted from lectin-reactive IgG was no longer inhibitory, suggesting that the effect of IVIg on T cells was the consequence of lectin neutralization, possibly by interaction with glycans present in F(ab')(2) portion of IgG molecules. Our results challenge the previously widely accepted notion that IVIg exerts its anti-inflammatory effects by acting directly on T cells and suggest that effects of IVIg observed in treated patients are rather a consequence of the recently reported inhibitory effect of IVIg on antigen presentation.     

Immunomodulation of autoimmune and inflammatory diseases with intravenous immunoglobulin

Abstract Intravenous immunoglobulin (IVIg) has been used in the treatment of primary and secondary antibody deficiencies for over two decades. Since the early 1980s, the therapeutic efficacy of IVIg has been established in idiopathic thrombocytopenic purpura, Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, myasthenia gravis, dermatomyositis and Kawasaki syndrome, and the prevention of graft versus host disease in recipients of allogeneic bone marrow transplants. Its use has also been reported in a large number of other autoimmune and systemic inflammatory conditions. In this review, we discuss the mechanisms by which IVIg exerts immunomodulatory effects in immune pathologies.     

Role of natural antibodies in immune homeostasis: IVIg perspective

Intravenous immunoglobulin (IVIg) has increasingly been used for the treatment of autoimmune and systemic inflammatory diseases in addition to supportive therapy of immunodeficient patients. Although a considerable progress has been made in understanding the mechanisms by which IVIg exerts immunomodulatory functions in these diseases, they remain not fully elucidated. The mode of action of IVIg is complex, involving interference with activation of complement and the cytokine network, modulation of: idiotype network, expression of Fc receptors, and activation, differentiation and effector functions of T and B cells and of antigen-presenting cells such as dendritic cells. The therapeutic effects of IVIg most likely reflect the functions of natural antibodies in maintaining immune homeostasis in healthy individuals.     

Biologically active anti-nerve growth factor antibodies in commercial intravenous gammaglobulin

Neurotrophins are regulators of development, survival and function of neuronal and non-neuronal cells, one of the most important of which is nerve growth factor (NGF). Previous studies have demonstrated the presence of antibodies to NGF in normal human serum. It would therefore be predicted that antibodies to NGF would also be present in commercial intravenous gammaglobulin (IVIg). It has been shown in the present investigation that ELISA can detect anti-NGF antibodies in IVIg. The functional activity of these antibodies has been demonstrated after affinity purification, by their inhibitory effects upon (a) the proliferation of the NGF-responsive rat pheochromocytoma cell line PC-12, (b) the differentiation of PC-12 cells as determined by neurite outgrowth. All batches of commercially tested IVIg contained anti-NGF antibodies. Since NGF has an important role in the inflammatory immune response and in cell growth and differentiation, these findings may (a) facilitate our understanding of the mechanisms of action of IVIg, (b) indicate new disease states in which IVIg or its derivatives may exert beneficial effects.     

In vivo administration of intravenous immunoglobulin (IVIg) can lead to enhanced erythrocyte sequestration.

Enhanced erythrocyte sequestration is one of the very few major adverse effects of intravenous immunoglobulin (IVIg). IVIg contains high molecular weight IgG complexes ( approximately 300 kDa) which, in the presence of serum, mimic immune complexes by activating complement, binding to CR1 of red blood cells (RBC) (CD35) and mediating erythrophagocytosis. Four of seven patients undergoing IVIg therapy showed significant drops in haematocrit and haemoglobin that were not due to isoantibodies in the IVIg. Prior to treatment, patients' RBC carried IgG and complement (C') 3d that were not bound as immune complexes via CR1 (CD35). The patients whose RBC bound immune complex-like moieties and showed drops in haematocrit and haemoglobin subsequent to IVIg were young adults (22-35 years); older patients (50-69 years) showed no ill effects. In the presence of complement, RBC of young patients bound IVIg complexes in vitro while those of older patients did not. It is not the absolute levels of erythrocyte-associated IgG or C'3 fragments, neither pre- nor post-therapy, which are predictive of IVIg associated decreases in haematocrit and haemoglobin levels. Patient age and RBC inability to bind the IVIg immune complex-like moieties in vitro both appear to be predictors of resistance to sequestration after in vivo treatment with IVIg.     

Immunoglobulines intraveineuses dans les maladies auto-immunes et inflammatoires : au-delà d’une simple substitution

Despite their widespread use since many years in autoimmune and inflammatory disorders, the mechanisms of action of IVIg have not been completely understood. These mechanisms depend on Fc and/or F(ab’)2. IVIg interacts with the different components of the immune system: Fc receptors, complement, cytokines, T and B lymphocytes, dendritic cells, granulocytes and NK cells. Here, we discuss the recent advances in the understanding of the mechanisms of action of IVIg, in particular the importance of the sialylated Fc fragment. These advances maybe help us conceive better therapeutic strategies against autoimmune and inflammatory disorders.     

Novel cross-reactive anti-idiotype antibodies with properties close to the human intravenous immunoglobulin (IVIg).

The most important link between the immune network theory and clinically useful therapies so far is the use of human intravenous immunoglobulin (IVIg) in the treatment of autoimmune diseases. Although still controversial, one of the main mechanisms that has been postulated for the in vivo effects of IVIg, is the selection of immune repertoires through idiotypic interactions. We describe here anti-idiotype IgG monoclonal antibodies (MAbs), which were obtained by immunization of syngeneic mice (Balb/c) with an anti-ganglioside antibody. These anti-idiotype MAbs show multiple idiotypic connections and share some of the properties of the IVIg pool. The antiidiotype (Ab2) MAbs B7 and 34B7 showed heterogeneous binding with the idiotypes of several anti-ganglioside antibodies, MAbs obtained from splenocytes of nonimmunized newborn mice, F(ab')2 fragments of IgG human myeloma proteins, and nonimmunoglobulin antigens. The recognition pattern of the B7 MAb to the idiotypes of human immunoglobulins was also studied using a phage display library obtained from the variable region genes of an asymptomatic AIDS patient and also F(ab')2 fragments obtained from an IVIg pool of healthy human donors. We also demonstrated that these MAbs produced some of the in vitro effects reported for the human IVIg pool, such as the inhibition of cell proliferation of human B and T cell lines and of normal human lymphocytes activated with different mitogens. Another striking property of the MAb B7 was its ability to induce a dose-dependent specific antibody T-cell response in vivo in syngeneic mice. Both anti-idiotype MAbs showed anti-metastatic effect in vivo when injected intravenously to mice inoculated with MB16-F10 melanoma cells. The antimetastatic effect of the antiidiotype MAbs was not observed in athymic mice inoculated with the same tumor. This kind of antibody can become an interesting tool for further exploration of the role of idiotypic network connections in the regulation of the immune system and to study the effects of interventions on network connectivity in experimental autoimmune disease, using a reagent better chemically defined than the IVIg pool.     

Anti-inflammatory effect of intravenous immunoglobulin mediated through modulation of complement activation

Complement activation by immune complexes is well-known. In the course of autoimmune disease, acute and chronic complement activation is the primary inducer of inflammation and tissue damage. Polyconal, polyspecific intravenous immunoglobulin (IVIg) preparations are a therapy of choice in a variety of autoimmune and inflammatory diseases. This review describes mechanisms by which IgG reduces complement activation or interferes with the action of proinflammatory complement-derived proteins. The known interference of IVIg with the biological activity of complement-derived proinflammatory proteins does not affect the generation of these potentially dangerous products, but can limit their devastating effects. Therefore, we embarked on studies on IVIg’s potential to attenuate complement activation and thus to prevent further generation of such dangerous molecules. We present here a revised view of how the central event of complement activation—namely, complement amplification—operates on a molecular level and how IVIg, with its physiological autoantibodies directed against some complement proteins, is able to downregulate amplification of complement C3 activation. Finally, we summarize results of a study in which clinical effects of IVIg and attenuation of complement activation were assessed. We propose that the anti-inflammatory effect of IVIg in a wide range of autoimmune diseases might be explained, at least in part, by attenuation of complement amplification.     

Broad requirement for terminal sialic acid residues and FcγRIIB for the preventive and therapeutic activity of intravenous immunoglobulins in vivo

Intravenous immunoglobulin (IVIg) therapy is widely used to treat a variety of autoimmune diseases including immunothrombocytopenia, chronic inflammatory demyelinating polyneuropathy, and more recently autoimmune skin blistering diseases. Despite this well‐documented clinical success, the precise molecular and cellular mechanisms underlying this immunomodulatory activity are discussed controversially. In particular, the clinically relevant therapeutic pathway of IVIg‐mediated immune modulation has not been studied in detail. In the present study, we use four independent in vivo model systems of auto‐Ab‐mediated autoimmune disease to identify a common pathway explaining IVIg activity under therapeutic conditions in vivo. We show that irrespective of the in vivo model system, IVIg activity is strictly dependent on the presence of terminal sialic acid residues and the inhibitory FcγRIIB under preventive as well as therapeutic treatment conditions. In contrast, specific ICAM3 grabbing nonintegrin related 1, previously demonstrated to be essential under preventative treatment conditions, showed a disease‐specific impact on IVIg‐mediated resolution of established autoimmune disease.